Proinflammatory CXCL12-CXCR4/CXCR7 Signaling Axis Drives Myc-Induced Prostate Cancer in Obese Mice.
Proinflammatory CXCL12-CXCR4/CXCR7 Signaling Axis Drives Myc-Induced Prostate Cancer in Obese Mice.
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DOI：
10.1158/0008-5472.can-17-0284
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发表时间：
2017-09-15
期刊：
影响因子：
11.2
通讯作者：
DiGiovanni J
中科院分区：
文献类型：
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作者：
Saha A;Ahn S;Blando J;Su F;Kolonin MG;DiGiovanni J
肥胖是前列腺癌（PCa）进展的一个预后危险因素，然而，其分子机制尚不清楚。在这项研究中，我们为促炎性 CXCL12-CXCR4/CXCR7 信号轴在肥胖驱动的 HiMyc 前列腺癌小鼠模型中的作用提供了临床前概念证明。对 6 个月大的肥胖 HiMyc 小鼠的前列腺周围白色脂肪组织 (ppWAT) 的基质血管部分 (SVF) 进行分析，发现编码各种趋化因子、细胞因子、生长因子和血管生成介质的 mRNA 显着增加，其中 CXCL12 是上调最显着的基因之一。对肥胖 HiMyc 小鼠腹侧前列腺组织进行免疫荧光染色显示，基质区室中 CXCL12 水平高，肿瘤上皮区室中 CXCR4 和 CXCR7 染色水平高。与来自非致瘤性前列腺上皮细胞系（NMVP 细胞）的蛋白质裂解物相比，源自 HiMyc 肿瘤的 PCa 细胞系（HMVP2 和衍生细胞系）显示 CXCR4 和 CXCR7 的蛋白质表达增加。 CXCL12 治疗刺激 HMVP2 细胞的迁移和侵袭，但不刺激 NMVP 细胞。 CXCL12 对 HMVP2 细胞的这些作用被 CXCR4 拮抗剂 AMD3100 以及 CXCR4 或 CXCR7 的敲低所抑制。 CXCL12 治疗还在 HMVP2 细胞中产生 STAT3、NFkB 和 MAPK 信号传导的快速激活，该信号传导再次被 AMD3100 或 CXCR4 或 CXCR7 敲低所减弱。总的来说，这些数据表明基质细胞分泌的 CXCL12 激活 PCa 细胞的侵袭性，并可能在驱动肥胖症肿瘤进展中发挥作用。靶向 CXCL12-CXCR4/CXCR7 轴可能会带来新的方法来抵消肥胖对 PCa 进展的影响。
Obesity is a prognostic risk factor in the progression of prostate cancer (PCa), however, the molecular mechanisms involved are unclear. In this study, we provide preclinical proof of concept for the role of a pro-inflammatory CXCL12-CXCR4/CXCR7 signaling axis in an obesity-driven mouse model of HiMyc prostate cancer. Analysis of the stromal vascular fraction (SVF) from periprostatic white adipose tissue (ppWAT) from obese HiMyc mice at 6 months of age revealed a dramatic increase in mRNAs encoding various chemokines, cytokines, growth factors and angiogenesis mediators, with CXCL12 among the most significantly upregulated genes. Immunofluorescence staining of ventral prostate tissue from obese HiMyc mice revealed high levels of CXCL12 in the stromal compartment as well as high staining for CXCR4 and CXCR7 in the epithelial compartment of tumors. PCa cell lines derived from HiMyc tumors (HMVP2 and derivative cell lines) displayed increased protein expression of both CXCR4 and CXCR7 compared to protein lysates from a non-tumorigenic prostate epithelial cell line (NMVP cells). CXCL12 treatment stimulated migration and invasion of HMVP2 cells but not NMVP cells. These effects of CXCL12 on HMVP2 cells were inhibited by the CXCR4 antagonist AMD3100 as well as knockdown of either CXCR4 or CXCR7. CXCL12 treatment also produced rapid activation of STAT3, NFkB, and MAPK signaling in HMVP2 cells which was again attenuated by either AMD3100 or knockdown of CXCR4 or CXCR7. Collectively, these data suggest that CXCL12 secreted by stromal cells activates invasiveness of PCa cells and may play a role in driving tumor progression in obesity. Targeting the CXCL12-CXCR4/CXCR7 axis could lead to novel approaches for offsetting the effects of obesity on PCa progression.